Intermediates for the preparation of 2-imidazoline-5-ones

ABSTRACT

Novel 2-thio-thiazolidine-5-one compounds useful as intermediates for fungicidal 2-imidazoline-5-ones are disclosed.

The present invention relates to novel products which may be used asintermediates for the preparation of 2-imidazolin-5-ones for fungicidaluse. The invention also relates to the processes for the preparation ofthese novel products and to a process which is useful for obtainingthese 2-imidazolin-5-ones from these novel intermediates.

2-Imidazolin-5-ones for fungicidal use are known, in particular fromEuropean patent applications EP 551,048, EP 599,749 and BP 629,616 andfrom International application WO 93/24467.

One aim of the present invention is to propose novel intermediates whichallow the preparation of these 2-imidazolin-5-ones.

Another aim of the present invention is to propose a novel route ofaccess to fungicidal 2-imidazolin-5-ones which is of improved safety.

The subject of the invention is thus, firstly, 2-thiothiazolidin-5-onesof general formula (I):

in which:

R¹ is a C₁-C₃ alkyl or phenyl radical,

R¹ is an aryl group chosen from phenyl or pyridyl, which is optionallysubstituted with 1 to 3 groups chosen from a halogen atom, a nitro orcyano group and a C₁-C₃ alkyl or C₁-C₃ alkoxy radical;

with the exception of 4-ethyl-4-phenyl-2-thiothiazolidin-5-one.

The subject of the invention is also the salified form, as well as thestereoisomers of the compounds of formula (I). The subject of theinvention is, in particular, the optical isomers resulting from thepresence of an asymmetric carbon, and most particularly, when theradicals R¹ and R³ are different, the optical isomers resulting from thepresence of the asymmetric carbon bearing R¹ and R³. These opticalisomers are optically pure compounds or compounds that are highlyenriched in one enantiomer. In the following text, the expressionoptically active compound that is highly enriched in a given enantiomerit understood to refer to a compound containing at least 80%, preferablyat least 90%, of this enantiomer. All these compounds are considered asbeing included in formula (I) defined above.

Among the compounds of formula (I), those are preferred for which:

R¹ represent a C₇-C₃ alkyl radical,

R² represents a phenyl optionally substituted with a halogen atom, acyano or nitro group or a methyl or methoxy radical,

Even more particularly, among the compounds of formula (I), those forwhich R³ is a phenyl and R¹ is a methyl are preferred.

According to a very advantageous variant of the invention, the compoundof formula (I) in which;

R¹ is a methyl and

R³ is a phenyl,

is an enantiomer relative to the asymmetric carbon bearing R¹ and R².

In the present description, all the groups appearing in the chemicalformulae which follow, and which have already been defined in thegeneral formula (I), retain the same meaning unless specifically statedotherwise. The alkyl radicals mentioned in the present text may belinear or branched.

One mode of preparation of the compound of formula (I) is now described.This mode of preparation is indicated in the case of compounds which areracemic relative to the carbon bearing the radicals R¹ and R². A personskilled in tho art may, however, use these same reactions %when he orshe wishes to obtain a compound of formula (I) which is enantiomericrelative to the carbon bearing R¹ and R². The reason for this is thatthe reactions indicated below are entirely stereoselective, in the sensethat they do not result in any change in the absolute configuration ofthis same carbon.

The compound of formula (I) may be obtained by reacting a compound offormula (II) with carbon sulphide, in a solvent or a mixture ofsolvents, optionally in the presence of a base, at a temperature ofbetween 0° C. and +50° C., according to the following scheme:

in which R³ is an amino or hydroxyl group or a linear or branched alkoxyradical containing from 1 to 6, preferably from 1 to 3, carbon atoms ora benzyloxy radical optionally substituted with a halogen atom.

The base optionally used may be an inorganic base ouch as analkali-metal or alkaline-earth metal hydroxide or carbonate or anorganic base such as a primary, secondary or tertiary amine. It may beused in a base/compound II ratio (expressed as number of moles) ofbetween 0.05 and 1.2, preferably between 0.1 and 1.

In this scheme, the compound of formula (III) may be isolated as anintermediate, in the case where a base is used, in the form of a salt.

Solvents which may be used are water, others, cyclic ethers, alkylesters, dipolar solvents such as acetonitrile, alcohols of 1 to 4 carbonatoms, aromatic solvents, preferably toluene, dichloromethane orchloroform, and carbon sulphide. Mixtures of solvents which may be usedare the mixture of one or more alcohols with one or more of theabovementioned solvents.

When R³ is a hydroxyl group, it is preferred to use water as solvent.

When R³ is other than a hydroxyl group, it is preferred to use analcohol/water mixture as solvent.

In the case where the compound of formula (III) is isolated, it may beconverted directly into compound (I) by heating to a temperature rangingfrom 25° C. to the reflux temperature of the solvent used. Theconversion of intermediate compound (III) into compound (I) may also becarried out by treatment with a strong acid which is either an inorganicacid such as hydrochloric acid or sulphuric acid, or an organic acidsuch an trifluoroacetic acid.

It is preferred to carry out this process in the absence of base or at atemperature of between 20 and 40° C. In this case, the compound offormula (III) is not isolated.

Other modes of the procedure which allow compound (I) to be preparedstarting from (II) are described by A. C. Davis and A. J. Levy in J.Chem. Soc., pp. 2419-25 (1951) or by K. Hofmann et al. in J. Am. Chem.Soc., vol 74, pp. 470-476 (1952).

The α-amino aster of formula (II) in which R³ is an alkoxy radical maybe obtained by esterification of the corresponding α-amino acidsaccording to a procedure similar to that described by M. Brenner and W.Huber in Helv Ch. Acta. (1953), volume 36, pages 1109-1115.

The α-amino amide of formula (II) in which R₃ is an amino group may beobtained from an amino ester by the action of ammonia as described by J.A. Garbarino in Ann. Chimica Ital. vol. 59, pp. 841-849 (1969).

The α-amino acids are prepared by reactions and methods that are knownper se.

When the compound of formula (II) is amino ester enantiomer, it may baobtained in particular by:

diastereoselective amination of a prochiral compound followed bydeprotection of the chiral couple as described by R. S. Atkinson et al.,Tetrahedron, 1992, 48, pp. 7713-30, or by

resolution of the corresponding racemic mixture with a chiral compound,as described by Y. Sugi and S. Mitsui, Bull. Chem. Soc. Japan, 1969, 42,pp. 2984-39, or alternatively by

esterification of a chiral amino acid, as described by D. J. Cram etal., J. Am. Chem. Soc., 1961, 83, pp. 2193-89.

When the compound of formula (II) is an amino amido enantiomer, it maybe obtained either starting from a chiral amino ester or by resolutionof the corresponding racemic mixture, as described by H. Dahn et al. inHelv. Chim. Acta, vol. 53, pp. 1370-1378 (1970).

The 2-thiothiazolidin-5-ones of formula (I) are useful for thepreparation of fungicidal 2-imidazolin.-S-ones of formula (IV):

in which:

M represents an oxygen or sulphur atom

R³⁰ represents a linear or branched alkyl radical containing from 1 to 6carbon atoms or a linear or branched haloalkyl radical containing from 1to 6 carbon atoms;

R⁴ represents a hydrogen atom or an acyl radical;

R⁵ represents an aryl or heteroaryl radical chosen from: phenyl,naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl,benzothienyl, furyl, bensofuryl, quinolyl, isoquinolyl ormethylenedioxyphenyl, each of these radicals optionally beingsubstituted with 1 to 7 groups, which may be identical or different,preferably from 1 to 3, chosen from the meanings of R⁵¹ defined below;

R⁵¹ ¹ represents:

a halogen atom or

an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio oralkylsulphonyl radical, which is linear or branched, of 1 to 6 carbonatoms, or

a cycloalkyl, halocycloalkyl, alkenyloxy, alkynyloxy, alkenylthio oralkynylthio radical of 3 to 6 carbon atoms, or

a nitro or cyano group, or

an amino radical optionally mono- or disubstituted with an alkyl or acylradical of 1 to 6 carbon atoms or alkoxycarbonyl radical of 2 to 6carbon atoms

as well as the agriculturally acceptable salified forms of thesescompounds and their stereoisomers, in particular, when R¹ and R² aredifferent, the optical isomers resulting from the presence of theasymmetric carbon bearing the radicals R¹ and R³.

The preparation of the fungicidal compounds of formula (IV) startingfrom the 2-thiothiazolidin-5-ones of formula (I) which form the subjectof the invention is now described, according to a process which may beused either in a racemic series or in an enantiomeric series.

The compound of formula (I) is reacted with a compound of formula (V) ina solvent and at a temperature of between +20° C. and +100° C.,preferably between 40 and 80° C., according to the following scheme:

Solvents which may be used are, for example, dioxane, a dipolar aproticsolvent, in particular N-methylpyrrolidone, dimethylformamide, dimethylsulphoxide or acetonitrile, an alcohol comprising from 1 to 4 carbonatoms and more particularly methanol, an aromatic solvent and morespecifically pyridine or monochlorobenzene.

It is preferred to carry out this reaction using a catalyst chosen froma tertiary amino such as triethylamine or tributylamine, or an organicsalt of this amine, such as tributylamine acetate. This catalyst ispresent in a catalyst/compound (I) proportion (expressed as number ofmoles) ranging from 0.05 to 1, preferably from 0.1 to 0.5. In this case,improved purity in obtained.

The thiohydantoin of formula (VI) is converted into 2-imidazolin-5-oneof formula (IV) according to a process described in one of the patentapplications EP 551,048, EP 599,749 and EP 629,616.

The examples which follow are given purely by way of illustration of thecompounds and preparation processes which form the subject of theinvention. They do not in any way limit this invention. The structure ofthe derivative illustrated was established using at least one of thefollowing spectral techniques: proton NMR spectrometry, carbon 13 NMRspectrometry, infrared spectrometry and mass spectrometry, as well asthe usual methods for measuring optical rotations.

EXAMPLE No. 1 Preparation of(4S)-4-methyl-4-phenyl-2-thiothiazolidin-5-one from an amino amide

3.26 g (20 mmol) of (2S)-2-amino-2-phenylpropionamide, 6 ml (100 mmol)of carbon sulphide and 4 ml of acetonitrile are introduced into a 50 mlround-bottomed flask fitted with a mechanical stirrer. The heterogeneousmedium is kept stirring for 20 h at 20° C. After distillation undervacuum of the excess carbon sulphide and the acetonitrile, and afterpurification and filtration, 3.70 g of(4S)-4-methyl-4-phenyl-2-thiothiazolidin-5-one are obtained in the formof a white solid melting at 104° C., corresponding to a yield of 93%.

EXAMPLE No. 2 Preparation of(4S)-4-methyl-4-phenyl-2-thiothiazolidin-5-one from an amino ester

2 g (11.1 mmol) of methyl (28)-2-amino-2-phenylpropionate, 15 ml oftetrahydrofuran, 1.92 ml (13 mmol) of triethylamine and 0.78 ml (13mmol) of carbon sulphide are introduced into a 25 ml test tube fittedwith a magnetic stirrer. After hermetic closure, the test tube ismaintained at 45° C. and the homogeneous medium is kept stirring for 4 hat this temperature.

After cooling and purification, 2 g of (4S) -4-methyl-4-phenyl-2-thiothiazolidin-5-one are obtained in the to the form of a whitepowder, i.e. a yield of

EXAMPLE No. 3 Preparation of(4S)-4-methyl-4-phenyl-1-phenylamino-2-thiohydantoin

893 mg (4 mmol) of (4S)-4-methyl-4-phenyl-2-thiothiazolidin-5-one, 8 mlof acetonitrile and 100 μl (0.4 mmol) of tributylamine are introducedinto a 25 ml round-bottomed flask fitted with a magnetic stirrer. Themixture is heated to 70° C. and a solution of 520 mg (4.8 mmol) ofphenylhydrazine in 4.5 ml of acetonitrile is then run in over 2 h. Thereaction medium is heated at 80° C. for 6 h. After cooling, theacetonitrile is removed by distillation under reduced pressure. Afterpurification, 975 mg of(4S)-4-methyl-4-phenyl-1-phenylamino-2-thiohydantoin are obtained in theform of a white solid melting at 167° C., the purity of which, measuredby HPLC, is 100%, i.e. a yield of 82%.

EXAMPLE No. 4 Preparation of(4S)-4-methyl-4-phenyl-2-thiothiazolidin-5-one from(2S)-2-amino-2-phenylpropionic acid

11 g (10⁻² mol) of (28)-2-amino-2-phenylpropionic acid (in the form of amixture containing 15% by weight of amino acid in solid NaCl), 10 ml ofN-methylpyrrolidone, 0.8 g (2×10⁻² mol) of NaOH pellets and then 1.8 ml(3×10⁻² mol) of carbon disulphide are successively introduced into a 50ml round-bottomed flask fitted with a magnetic stirrer.

After hermetic closure, the reaction medium in heated at 60° C. for 5hours with vigorous stirring. After cooling, 50 ml of water and then 5,4ml of concentrated H₂SO₄ are added to the reaction medium. The organicphase is extracted, washed, dried and then concentrated.(45)-4-Methyl-4-phenyl-2-thiothiazolidin-5-one is obtained in a yield of84%.

What is claimed is:
 1. A process for preparing a compound having theformula (VI):

wherein: R₁ is a C₁-C₃ alkyl or phenyl radical; R₂ is a phenyl orpyridyl radical, said radical being optionally substituted with 1 to 3substituents selected from the group consisting of a halogen atom, anitro or cyano group and a C₁-C₃ alkyl or C₁-C₃ alkoxy radical; R₄ is ahydrogen atom or an acyl radical; and R₅ is a phenyl, naphthyl, pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, benzothienyl, furyl,benzofuryl, quinolyl, isoquinolyl or methylenedioxyphenyl radical, saidradical being optionally substituted with 1 to 7 groups, which are thesame or different, selected from the meanings of R⁵¹; R⁵¹ is: a halogenatom; an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthioor alkylsulphonyl radical, which is linear or branched and has 1 to 6carbon atoms; a cycloalkyl, halocycloalkyl, alkenyloxy, alkynyloxy,alkenylthio or alkynylthio radical having 3 to 6 carbon atoms; a nitroor cyano group; or an amino radical which is optionally mono- ordisubstituted with an alkyl or acyl radical having 1 to 6 carbon atomsor an alkoxycarbonyl radical of 2 to 6 carbon atoms; said processcomprising reacting a compound having formula (I) with a compound havingformula (V) below in a solvent and at a temperature of between 20° C.and 100° C., according to the scheme:


2. A process according to claim 1, wherein R₁ and R₂ are different andthe compound is an enantiomer relative to the asymmetric carbon atombearing R₁ and R₂.
 3. A process according to claim 1, wherein: R₁ is aC₁-C₃ alkyl radical; and R₂ is a phenyl radical optionally substitutedwith a halogen atom, a nitro or cyano group or a methyl or methoxyradical.
 4. A process according to claim 2, wherein: R₁ is a C₁-C₃ alkylradical; and R₂ is a phenyl radical optionally substituted with ahalogen atom, a cyano or nitro group or a methyl or methoxy radical. 5.A process according to claim 3, wherein R₂ is a phenyl radical and R₁ isa methyl radical.
 6. A process according to claim 4, wherein R₂ is aphenyl radical and R₁ is a methyl radical.
 7. A process according toclaim 6, wherein the compound of formula (I) is(4S)-4-methyl-4-phenyl-2-thiothiazolidin-5-one.
 8. A process accordingto claim 1, said process being carried out in the presence of a catalystwhich is a tertiary amine or salt thereof, said catalyst being presentin a catalyst/compound of formula (I) proportion of from 0.05 to
 1. 9. Aprocess according to claim 8, wherein the catalyst is present in acatalyst/compound of formula (I) proportion of from 0.1 to 0.5.
 10. Aprocess according to claim 8, wherein the compound of formula (I) is(4S)-4-methyl-4-phenyl-2-thiothiazolidin-5-one.
 11. A process accordingto claim 9, wherein the compound of formula (I) is(4S)-4-methyl-4-phenyl-2-thiothiazolidin-5-one.
 12. A process accordingto claim 8, wherein the catalyst is triethylamine or tributylamine, oran organic salt thereof.
 13. A process according to claim 9, wherein thecatalyst is triethylamine or tributylamine, or an organic salt thereof.14. A process according to claim 10, wherein the catalyst istriethylamine or tributylamine, or an organic salt thereof.
 15. Aprocess according to claim 11, wherein the catalyst is triethylamine ortributylamine, or an organic salt thereof.
 16. A process according toclaim 8, wherein the reactant of formula (V) is phenylhydrazine.
 17. Aprocess according to claim 9, wherein the reactant of formula (V) isphenylhydrazine.
 18. A process according to claim 10, wherein thereactant of formula (V) is phenylhydrazine.
 19. A process according toclaim 11, wherein the reactant of formula (V) is phenylhydrazine.
 20. Aprocess according to claim 19, comprising reacting(4S)-4-methyl-4-phenyl-2-thiothiazolidin-5-one with phenylhydrazine inthe presence of tributylamine to afford(4S)-4-methyl-4-phenyl-1-phenylamino-2-thiohydantoin.